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Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.

Daniel Roth of the Hospital for Sick Kids in Canada and colleagues will test whether endocrine factors cause stunting in early infancy. They will analyze parathyroid hyperactivity in a cohort of infants from Bangladesh, where stunting is estimated to affect almost half of all children under the age of 5. To uncover the mechanisms responsible for this hyperactivity, they will conduct a vitamin D supplementation trial and analyze maternal, cord, and infant plasma specimens for evidence of dysregulation of the parathyroid-­vitamin D axis. Their goal is to understand the cause of widespread vitamin D deficiency in the region, which is under­-appreciated, and its linkage to early growth retardation.

Theresa Gyorkos of McGill University in Canada and colleagues will investigate whether treating worm infections in lactating women has a beneficial effect on breast milk production and on infant and maternal health. They will conduct a double blind, randomized, controlled trial in Peruvian mothers following in-hospital delivery, and analyze the effect of de-worming on quantity and quality of breast milk, maternal anemia, and infant growth and morbidity, over a 24-month period. Their ultimate aim is to improve the health of both mother and child by informing global policy on maternal postpartum care.

Kevin Kain of the University Health Network and the University of Toronto in Canada will investigate malaria infections of the placenta to reveal specific roles of the immune response that lead to preterm birth, low birth weight, and stillbirth. This project will focus on discovering biomarkers to identify at-risk pregnancies as well as new interventions to prevent adverse pregnancy outcomes. Funding partners: Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) and Bill & Melinda Gates Foundation.

David Olson from the University of Alberta in Canada will work to better understand how infections can cause preterm birth. Using animal models and later in studies of women in low-income countries, he and his team will investigate multiple mediators of inflammation in the uterus early in pregnancy, as well as test new diagnostics and therapeutics that can identify women at risk, modulate the inflammatory response, and prolong pregnancy. Funding partners: Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) and Bill & Melinda Gates Foundation.

Peter Gluckman of the University of Auckland in New Zealand and colleagues will test whether intrauterine growth retardation and childhood stunting, which are commonly seen in developing countries, are caused by epigenetic changes that can be corrected in pregnancy and infancy by modifying nutrition. Stunting is associated with many negative outcomes including decreased cognitive ability and immune function. Using epigenetic analyses, and clinical and epidemiological approaches in stunted and control children from Jamaica, Ghana and Singapore they will identify underlying pathophysiological mechanisms of stunting that can act as targets for intervention. The long-­term goal is to prevent infant stunting and its associated adverse consequences.

David MabeyLondon School of Hygiene and Tropical MedicineLondon, United Kingdom

Grand Challenges in Global Health

Achieving Healthy Growth

1 Jan 2012

David Mabey of the London School of Hygiene and Tropical Medicine in the United Kingdom and his team will test whether treatment with the broad­-spectrum antibiotic azithromycin can prevent growth faltering linked to environmental enteropathy, which is prevalent in young children of developing countries. They will utilize a double blind, randomized, controlled trial of Malawian children aged 1­-60 months, and analyze growth over a two year period after a single administration of either the antibiotic or a placebo control. They will also analyze immune responses and composition of the intestinal microbiota to identify the molecular pathways underlying environmental enteropathy. Their aim is to improve growth and development in affected infants in low­-income countries.

Yun Yun Gong of Queen’s University Belfast in the United Kingdom and colleagues will identify mechanistic biomarkers of child stunting caused by the dietary contaminant aflatoxin, which is common in many parts of sub-Saharan Africa. They will determine the mechanism by which aflatoxin inhibits growth in early life using blood samples and growth charts from 300 children in Gambia and analyzing the relationship between aflatoxin exposure and changes in insulin-like growth factor signaling, epigenetic marks, and gene expression. Candidate biomarkers will be validated in an in vitro cell model of human liver, which is the primary target of aflatoxin, and used to drive future intervention strategies, such as hand-sorting food to reduce contamination, for ultimately improving child health.

Charles KingCase Western Reserve UniversityCleveland, Ohio, United States

Grand Challenges in Global Health

Achieving Healthy Growth

1 Jan 2012

Charles King of Case Western Reserve University in the U.S. and his team will study how chronic parasitic infections in pregnant mothers affect infant immunity and childhood development. Using existing and prospective maternal­-child cohorts in Kenya they will analyze the effect of parasitic infections, such as schistosomiasis and intestinal helminths, encountered in utero on subsequent infant vaccine responses, and on general growth and development later in childhood. They will also test whether specific anti­-parasitic treatment during pregnancy can improve childhood immunity and development.

Robin BernsteinGeorge Washington UniversityWashington, District of Columbia, United States

Grand Challenges in Global Health

Achieving Healthy Growth

1 Jan 2012

Robin Bernstein of the George Washington University in the U.S. and colleagues will undertake one of the most detailed longitudinal studies to date to examine the effects of epigenetic and hormonal factors on growth during the first 1000 days of life. Assessment of a variety of parameters, including infectious exposures and hormone levels, as well as epigenome and transcriptome analyses will be collected from the 13th week of gestation through infant and early childhood from a cohort of 200 Gambian children. These extensive data sets will reveal the mechanisms of growth faltering, and will aid in the development of targeted interventions to promote healthy infant growth and development.

Sean Limesand of the University of Arizona in the U.S., along with co-­investigators, will test whether infants with intrauterine growth restriction, caused during gestation by oxygen and nutrient deprivation, could benefit from pharmacological intervention using well­-characterized adrenergic drugs to improve skeletal muscle metabolism. Intrauterine growth restriction affects around 24% of babies born in developing countries and leads to perinatal morbidity and mortality. The team will perform intervention studies using the adrenergic drugs in a well­-defined sheep model of intrauterine growth restriction, and identify related biomarkers using placental tissue from affected human infants. These studies will increase understanding of the pathophysiological mechanisms underlying intrauterine growth restriction and could lead to new treatment options.

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